Lack of in vivo cross-resistance with 4′-thio-ara-C against drug-resistant murine P388 and L1210 leukemias

Abstract

Purpose 4’-Thio-β-D-arabinofuranosylcytosine (4’-thio-ara-C), which has shown a broad spectrum of antitumor activity against human tumor systems in mice and is undergoing clinical trials, was evaluated for cross-resistance to seven clinical agents in order to identify potentially useful guides for patient selection for further clinical trials of 4’-thio-ara-C and possible noncross-resistant drug combinations with 4’-thio-ara-C. Methods A drug-resistance profile for 4’-thio-ara-C, which was administered intraperitoneally daily for nine consecutive days, was obtained using seven drug-resistant P388 and L1210 leukemias that were implanted intraperitoneally in mice. Results Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin, etoposide, or paclitaxel) exhibited no cross-resistance to 4’-thio-ara-C. Leukemias resistant to camptothecin, cisplatin, and 5-fluorouracil were also not cross-resistant to 4’-thio-ara-C. Only the leukemia resistant to 1-β-D-arabinofuranosylcytosine was cross-resistant to 4’-thio-ara-C. Conclusions The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-β-D-arabinofuranosylcytosine and (2) the lack of cross-resistance seen with 4’-thio-ara-C may contribute to therapeutic synergism when 4’-thio-ara-C is combined with other agents.

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

“…17,446 In addition, crossresistance in multidrug resistant cell lines did not occur for thiarabine 47, suggesting that it potentially could be used in combination drug therapy. 451,452 Previously, a Phase I/II clinical trial showed positive results when using clofarabine 12 and cytarabine 4, having a proposed mechanism of increased cytarabine-5′-triphosphate concentration in cells. 453 These results led to a combination therapy of clofarabine 12 and thiarabine 47 study, which showed synergistic activity of 12 and 47 leading to delayed tumor growth in mice.…”

Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer

“…Although thiarabine (T-araC) is structurally similar to araC (Figure 12), the antitumor activity of T-araC against a variety of human tumor xenografts in mice is dramatically better than that of araC,70 a compound that does not demonstrate solid tumor activity in these animal models or in patients. T-araC has also demonstrated better activity than gemcitabine against various human tumor xenografts in mice.…”

Isolation and Characterization of a Murine P388 Leukemia Line Resistant to Thiarabine

“…Of special concern would be patients who have been treated previously with ara-C, because a P388 subline resistant to ara-C is cross resistant to thiarabine. [17] It is important to recognize that other mechanisms of resistance may be developed clinically. As always, none of the above approaches may be applied clinically without caution and concern for the recognized gap between preclinical prediction and clinical validation.…”